The research proposed seeks 1) to identify the molecular and cellular determinants for the selective uptake and lysosomal storage of Beta-glucuronidase by human fibroblasts in tissue culture, 2) to develop an ultrastructural histochemical procedure for the localization of Beta- glucuronidase with which to analyze the process of uptake and storage, 3) to study the distribution of exogenously administered Beta- glucuronidase in organs and cells of C3H mice which are moderately deficient with respect to the enzyme, and 4) to attempt to elicit mucopolysaccharide storage in C3H mice by overloading the limited capacity of the cells in these animals to hydrolyze Beta-glucuronide bond and further inhibiting the already low intracellular levels of Beta-glucuronidase with specific high affinity inhibitors. These studies are designed to provide a rational basis for the use of replacement enzymes in the treatment of lysosomal enzyme deficiency states.